Background: Various oral mesalazine formulations are available for treatment of IBD, but dissolution behaviours for each formulation in a physiological-based pH gradient considering the rapid fall in caecal pH (especially in ulcerative colitis) remain unclear.
Methods: In vitro release of 5-aminosalicylic acid (5-ASA) from different mesalazine formulations was assessed by a novel dynamic dissolution model simulating physiological-based gastrointestinal pH gradient prepared from compendial media. Dissolution profiles of one time-dependent (pH-independent) release formulation (Pentasa 500 mg tablets) and of two pH-dependent release formulations (Salofalk 500 mg granules, Mezavant 1200 mg tablets) at different pH values (1.2, 6.0, 6.8, 7.2, 6.0 or 5.5, 7.0) were determined. The pH drops to 6.0–5.5 in the caecum was taken into consideration.
Results: The time-dependent release formulation (Pentasa) lost 49% of 5-ASA in conditions simulating the stomach and small intestine at pH values of 1.2, 6.0, 6.8 and 7.2 (4 h) with 75% cumulative 5-ASA release in the caecum and colon (pH 6.0, 7.0; 7 h). Salofalk granules started to release mesalazine only at pH ≥6 and demonstrated 39% 5-ASA release in the small intestine (pH 6.0, 6.8 and 7.2; 3 h) with 100% cumulative 5-ASA release in the caecum and colon (pH 6.0, 7.0; 7 h). Mezavant started to release 5-ASA at pH 6.8 with 15% 5-ASA release in the small intestine (pH 6.8 and 7.2; 2 h) with 59% cumulative 5-ASA release in the caecum and colon (pH 6.0, 7.0; 7 h). Surprisingly, after pH drops to 6.0 or to 5.5 in the caecum 5-ASA release from all formulations (including pH-independent Pentasa) was slowed down. The following pH rise to 7.0 (distal colon) resulted in 5–15% increase in the release of 5-ASA.
Conclusions: Significant variations were observed between the dissolution profiles of various mesalazine formulations examined in a novel dynamic model simulating physiological-based gastrointestinal pH changes. The time-dependent release formulation (Pentasa) lost 50% of 5-ASA in the small intestine and released only 25% in the caecum and colon suggesting that it is not enough to create a high concentration of mesalazine in the distal colon. We suppose that the pH-dependent release formulation (Mezavant, pH >7) might not all fully release in vivo, as the gastrointestinal pH might not reach 7 and the rapid fall in caecal pH can slow down the release of 5-ASA. Salofalk granules (pH ≥6) revealed an optimal dissolution profile corresponding to the physiological gastrointestinal pH gradient, supporting its therapeutic use in distal ulcerative colitis. The reduction of 5-ASA release due to pH drops in the caecum should be considered when choosing oral mesalazine formulation for patients with distal ulcerative colitis.